TY - JOUR
T1 - Mutations in EFHC1 cause juvenile myoclonic epilepsy
AU - Suzuki, Toshimits
AU - Delgado-Escueta V, Antonio
AU - Aguan, Kripamoy
AU - Alonso, Maria E.
AU - Shi, Jun
AU - Haras, Yuji
AU - Nishidas, Motohiro
AU - Numata, Tomohiro
AU - Medina, Marco T.
AU - Takeuchi, Tamaki
AU - Morita, Ryoji
AU - Bai, Dongsheng
AU - Ganesh, Subramaniam
AU - Sugimoto, Yoshihisa
AU - Inazawa, Johji
AU - Bailey, Julia N.
AU - Ochoa, Adriana
AU - Jara-Prado, Aurelio
AU - Rasmussen, Astrid
AU - Ramos-Peek, Jaime
AU - Cordova, Sergio
AU - Rubio-Donnadieu, Francisco
AU - Inoue, Yushi
AU - Osawa, Makiko
AU - Kaneko, Sunao
AU - Oguni, Hirokazu
AU - Mori, Yasuo
AU - Yamakawa, Kazuhiro
N1 - Funding Information:
We thank the family members for participating in this study; Y. Itsukaichi, K. Yamada, Y. Tsutsumi, K. Shoda, E. Mazaki, A. Nitta, N. Okamura, C. Uchikawa, M. Hishinuma and S.G. Pietsch for their help; and the Research Resources Center of RIKEN Brain Science Institute for DNA sequencing analysis and generation of rabbit polyclonal antibodies. This work was supported in part by a grant from RIKEN Brain Science Institute, Japan. A.V.D.E. is partly supported by a grant from the US National Institutes of Health.
PY - 2004/8
Y1 - 2004/8
N2 - Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures1,2. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1)3-5. Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca2+ channel (Cav2.3). EFHC1 and Cav2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Cav2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca2+ currents that were reversed by the mutations associated with JME.
AB - Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures1,2. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1)3-5. Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca2+ channel (Cav2.3). EFHC1 and Cav2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Cav2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca2+ currents that were reversed by the mutations associated with JME.
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U2 - 10.1038/ng1393
DO - 10.1038/ng1393
M3 - Article
C2 - 15258581
AN - SCOPUS:3543026306
SN - 1061-4036
VL - 36
SP - 842
EP - 849
JO - Nature Genetics
JF - Nature Genetics
IS - 8
ER -